Patients with acute hypoxemic respiratory failure (AHRP) develop pulmonary edema and gas exchange impairment which results in significant morbidity and mortality. Mechanically ventilated patients with AHRF have better outcomes if alveolar epithelial integrity and rapid edema reabsorption occurs. Fluid is reabsorbed from the lungs by vectorial Na+ movement out of the alveoli, via apical Na+ channels and basolaterally located Na, K-ATPases. Previous studies have demonstrated that upregulation of the alpha-1 and beta-1 subunits of the Na+ pump increase Na, K-ATPase activity in the alveolar epithelial cells (AEC) in association with increased lung edema clearance. The PI has found that not only the alpha-1 but the alpha-2 Na, K-ATPase is expressed in AEC, especially in alveolar type I epithelial cells. Thus, the focus of this application is to determine the role of alpha-2 (as compared to alpha-1) Na, K-ATPase contributing to the lung's ability to clear edema as well as the mechanisms of regulation of the Na, K-ATPase in AEC by five interrelated specific aims. Completion of the experiments may provide novel information on the role and regulation of Na, K-ATPase and active Na+ transport in normal and injured lungs.